KR101500962B1 - Alpha-aminoamide derivatives useful in the treatment of psychiatric disorders - Google Patents

Abstract

The present invention relates to the pharmacological treatment of psychotic disorders which are schizophrenia and / or anxiety, wherein schizophrenia includes schizophrenia-related disorders such as short-term psychotic disorders, delusional disorders, schizoaffective disorders and schizophreniform disorders, Anxiety includes panic disorder, obsessive compulsive disorder (OCD), post traumatic stress disorder (PTSD), social phobia or social anxiety disorder, specific phobias and generalized anxiety disorder (GAD). The compounds of the present invention are useful for treating such mental disorders alone or in combination with other therapeutic agents effective in the treatment of schizophrenia and / or anxiety.

Description

[0001] The present invention relates to alpha-amino acid derivatives useful for the treatment of psychiatric disorders,

The present invention relates to? -Aminoamide derivatives useful for the treatment of mental disorders, which are schizophrenia and / or anxiety.

Mental disorders include, but are not limited to, schizophrenia, schizophreniform disorders, schizoaffective disorders, bipolar disorder (eg, type I bipolar disorder, type II bipolar disorder, mania, hypomania), non-bipolar mania, Tourette Psychotic disorders due to general drug conditions, Parkinson ' s disease, Parkinson ' s disease, Parkinson ' s disease, Parkinson ' Anxiety disorders such as psychotic disorders, substance-induced psychotic disorders or otherwise unspecified psychotic disorders, generalized anxiety disorders, panic disorders, post-traumatic stress disorders, impulse control disorders, panic disorders and dissociated conditions.

Schizophrenia and related disorders (short-term psychotic disorders, delusional disorders, schizoaffective disorders and schizophreniform disorders) are among the most severe and wasting forms of mental disorders.

The term "schizophrenia " as used herein and in the claims encompasses schizophrenia-related disorders such as short-term psychotic disorders, delusional disorders, schizoaffective disorders and schizophreniform disorders.

Schizophrenia is characterized by severe destruction of language, thought, perception, emotion, and ego, which are the most basic attributes of human beings. Symptoms of this include the following: experiencing internal voices or experiencing other sensations unrelated to a certain source (hallucination), giving unusual importance or meaning to ordinary things (paranoia), insisting on false personal beliefs (paranoia) Mental signs such as not touching are often included. Unilateral symptoms do not confirm the diagnosis, and more precisely, the diagnosis includes several signs and symptoms with impairment of occupational or social functioning.

Generally, symptoms of schizophrenia are classified into the categories of positive, confusing, negative, and cognitive. Positive symptoms are characterized by exaggerated or distorted normal function, and negative symptoms are characterized by diminished or disappearance of normal function. Disruptive symptoms include accidental disturbances and strange behavior.

Cognitive symptoms are defects in information processing and problem solving. A person can have one or all of the following categories of symptoms.

However, the typical treatment of schizophrenia is not very effective in the treatment of cognitive deficits in schizophrenia. A more recently developed treatment for schizophrenia, known as "atypical antipsychotic drugs," may have some effect on cognitive deficits, but does not persist or improve routine function.

Indeed, although there are a few data that demonstrate the efficacy of atypical antipsychotic drugs, the most common remedy prescribed for schizophrenia, psychosocial and cognitive behavior therapy still forms the basis of therapy in the treatment of cognitive disorders.

Cognitive disturbances, on the other hand, may be associated with a variety of disorders, such as schizophrenia, obsessive compulsive disorder, psychosis, bipolar disorder, anxiety, depression, attention deficit hyperactivity disorder, autism, dyslexia, Tourette's syndrome, mild cognitive impairment (MCI) Alzheimer's disease, Down's syndrome, traumatic brain injury, Huntington's disease, progressive nucleolus paralysis (HIV), stroke, vascular disease, Pick disease or Creutzfeldt-Jakob disease (E.g., Creutzfeldt-Jacob disease, multiple sclerosis (MS) and other white cortical disorders, Parkinson's disease) but is not established by the disease itself. However, those skilled in the art are well aware that it is important to distinguish between healing or alleviating certain symptoms that may be common in various diseases and treating the disease itself.

The object of the present invention is to provide a method for the treatment of schizophrenia (including schizophrenia-related disorders such as short-term psychotic disorders, delusional disorders, schizoaffective disorders and schizophreniform disorders) which is one of the most serious and consuming forms of psychiatric disorders Method.

Several hypotheses have been proposed to explain the pathogenesis of schizophrenia. Various neurotransmitter systems appear to be involved in pathology: hyperactivity of the dopaminergic circuits (Baumeister AA, Francis JL, J. Hist. Neurosci .; 2002 Sep; 11 (3): 265-77], imbalance of the gabaergic system (Squires RF, Saederup E, Neurochem. Res., 1991 Oct; 16 (10): 1099-111), impaired NMDA receptor status, and impaired cholinergic function (Woodruff-Pak DS, Gould TJ. Behav. Cogn. Neurosci. Rev. 2002 Mar; 1 (1): 5-20].

Despite many research achievements, the underlying pathophysiology of schizophrenia, including molecular causes and mechanisms, is now fairly incomplete, and despite advances in schizophrenia, patients who are resistant to treatment with neuroleptic and mood stabilizers Still exist, and there is a high demand for unmet medical needs.

By the end of the 1970s, the key pharmacological action of antipsychotic drugs was that they blocked dopamine D2 receptors in dopamine D2 receptors, particularly the midbrain-coupled dopamine pathway, leading to hyperactivity in this area, which is thought to cause positive symptoms of psychosis It is already known that the ability to reduce Unfortunately, it is not possible to block dopamine hyperactivity in only these specific areas, and therefore conventional antipsychotic drugs have serious side effects due to blockade of D2 receptors in other areas such as the black striatal pathway, which is responsible for the control of movement. More recent compounds, such as atypical antipsychotics, have antagonistic D2 receptor antagonism as well as serotonin receptor antagonism, and these properties result in fewer side effects and better disease suppression. On the other hand, in the action of antipsychotic drugs, a reduction in dopamine concentration is considered essential, but the regulation of glutamate delivery may be equally important. This hypothesis is supported by the fact that schizophrenia-like symptoms can be induced by NMDA antagonists in healthy volunteers. Over the years, it has been recognized that the powerful NMDA antagonist penicycline (PCP) induces abusers to develop psychotic symptoms very similar to schizophrenia (Morgan CJ et al., Neuropsychopharmacology. 2004 Jan; 29 (1): 208-18; Large CH, J. Psychopharmacol; 2007 May; 21 (3): 283-301).

All these data and the literature (Mouri A et al., Neurochem. Int .; 2007 Jul-Sep; 51 (2-4): 173-84; Lindsley CW et al., Curr. Top. Med. Chem. 2006; 6 (8): 771-85; Thornberg SA, and Saklad SR, Pharmacotherapy .; 1996 Jan-Feb; 16 (1): 82-93; Javitt DC. Int. Rev. Neurobiol .; 2007 78: 69-108] suggest that degradation of NMDA receptors may be associated with the induction of negative symptoms of the disease.

Patients with schizophrenia, Tourette's syndrome, panic disorder, and obsessive-compulsive disorder show deficits in the operative measurement of sensory gating: pre-pulse inhibition of surprise (PPI) (Geyer, Dial. Clin. Neurosci .; 2006 8 (1): 9-16; Geyer et al., Psycopharmacology; 2001 Jul; 156 (2-3): 117-54). One feature that is believed to cause certain signs of these diseases, including carelessness, distraction and cognitive deficits, is the diminished ability to filter irrelevant auditory stimuli. Similar PPI defects are caused by different pharmacological or developmental treatments in rats. This PPI deficiency experimentally induced in rats appears to provide a model of sensory gating defects in schizophrenia patients with surface and predictive validity. The destruction of the PPI of surprise in rodents is due to stimulation of the dopaminergic (DA) receptor induced by amphetamine or apomorphine, activation of the serotonin system by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors , And phencyclidine (PCP), which are mediated by N-methyl-D-aspartate (NMDA) receptors. Orthopedic and atypical antipsychotics, mood stabilizers, AChE inhibitors and nicotine are effective in restoring PPI breakdown caused by different treatments.

It is a further object of the present invention to provide a method for the treatment of psychiatric disorders defined as anxiety or anxiety disorders.

Anxiety or anxiety disorders include various different forms of abnormal morbid anxiety, fear and phobia, as noted below. Each anxiety disorder has different symptoms, but all symptoms have excessive irrational fear and fear. Anxiety disorders are understood to be panic disorder, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), social phobia (or social anxiety disorder), specific phobias and generalized anxiety disorder (GAD).

The main drugs used for anxiety disorders include anti-anxiety drugs (benzodiazepines and barbiturates), antidepressants and beta-blockers, which have different mechanisms of action. However, in some cases the therapeutic treatment of the disease and the effects on some symptoms that may be associated with it do not correspond. For example, several studies of cognitive disorders associated with anxiety have demonstrated that a reduction in anxiety after diazepam administration in anxiety patients is not accompanied by a decrease in cognitive impairment. This suggests that diazepam does not reduce anxiety-related cognitive impairment in patients with clinical anxiety (Cognitive Therapy and Research Volume 15, Number 6 / December, 1991, 459-467).

A number of adverse effects can be observed in the various types of drugs currently used for the psychiatric disorders described above, and thus high medical demands not met for these pathologies are recognized. For example, lithium salts may have a narrow therapeutic index, atypical antipsychotics may cause increased QTc interval and / or weight gain, anticonvulsants lead to sedation and cognitive impairment, antidepressants may be converted to mania ≪ / RTI > Although the side effect profile of each individual drug is significantly different, it is clear that the side effect profile of these drugs is undesirable.

In this respect, the present invention provides an innovative therapeutic method of mental illness identified as schizophrenia and anxiety using compounds of the present invention believed to have a strong therapeutic effect and a broad therapeutic index. In addition, there are frequent clinically significant accompanying psychiatric disorders.

Epidemiologic studies have shown a high incidence of anxiety disorders in schizophrenia, but their clinical relevance has not yet been recognized. Anxiety in schizophrenic patients can lead to increased risk of suicide, poor social function, and increased risk of relapse. Bayle et al. Found that 47.5% of patients with schizophrenia had a history of panic attack, 31.2% had a history of panic disorder prior to the onset of schizophrenia, and the treatment of panic disorder improved clinical and social outcomes (Eur Psychiatry 2001; 16-349-353).

Although studies of panic and obsessive compulsive disorders with schizophrenia have been conducted, clinical anxiety has been less focused on schizophrenia. People with social anxiety experience significant barriers to activities in daily life, occupational roles, and social relationships. Social anxiety is itself an impotence disorder, and patients with social anxiety disorder have more severe impotence. Patients with social anxiety are at higher risk of substance / alcohol abuse or dependence, and in schizophrenia this leads to higher impulsivity and suicide rates. Thus, evaluation and treatment of social anxiety disorders associated with schizophrenia patients will improve both clinical and social outcomes (Pallanti S. et al. - Am J Psychiatry (2004) 161: 53-58].

Because many of the patients suffering from schizophrenia (including schizophrenia-related disorders such as short-term psychotic disorders, delusional disorders, schizoaffective disorders and schizophreniform disorders) are observed to have an anxiety disorder at the same time, It also includes treatment of both diseases at the same time in the patient.

Conventional technology

WO 90/14334 is useful for the treatment of epilepsy and Parkinson's disease and is useful as a neuroprotective agent in degenerative diseases associated with pathological conditions such as normal aging or cerebral ischemia, and is useful as an antidepressant, hypnotic and / Substituted aminomido derivatives which act on the central nervous system (CNS), which can also be used (see Pevarello P. et al. (1998), "Synthesis and anticonvulsant activity of a new class of 2 - [(arylalkyl) amino] alkanamide derivatives ", J. Med. Chemistry, 41: 579-590).

WO 99/26614 discloses a method for the treatment or prevention of neurodegenerative conditions such as the treatment of neural injury after the whole brain and focal ischemia, neurodegenerative colorimetric sclerosis (ALS), and the treatment, prevention or alleviation of pain, Substituted aminomide derivatives which are active as antidiarrheal depressants, local anesthetics and antiarrhythmic agents and which are useful for the treatment or prevention of diabetic neuropathy.

WO 07/071311 discloses a method for the prevention, amelioration and treatment of neurological, psychiatric, cardiovascular, inflammatory, ocular, genitourinary and gastrointestinal disorders which are active as calcium and / or sodium channel modulators and which thus play a pathological role Useful 2-phenylethylamino derivatives are disclosed.

EP 1870097 A (corresponding to WO 2007/144153, published Dec. 21, 2007), published December 26, 2007, discloses a pharmaceutical composition for the treatment of schizophrenia, obsessive compulsive disorder, psychosis, bipolar disorder, anxiety, depression, Alzheimer's disease, Down's syndrome, traumatic brain disorder, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Treatment of cognitive impairment symptoms associated with various neuropsychiatric disorders such as Parkinson's disease, Huntington's disease, progressive nucleolus paralysis (HIV), stroke, vascular disease, Pick's disease or Creutzfeldt-Jakob disease, multiple sclerosis (MS) Amino-amide derivatives are disclosed.

DETAILED DESCRIPTION OF THE INVENTION [

Scope of invention

The present invention relates to an? -Aminoamide compound of the formula (I) for use in the treatment of psychotic disorders which are schizophrenia and / or anxiety disorders, optionally a single optically active isomer thereof or a mixture thereof or a pharmaceutically acceptable salt thereof Wherein the schizophrenia includes schizophrenia related disorders such as short-term psychotic disorders, delusional disorders, schizoaffective disorders and schizophreniform disorders, anxiety disorders include panic disorder, obsessive compulsive disorder, post-traumatic stress disorder, social phobia Or social anxiety disorder, specific phobia, and generalized anxiety disorder.

Formula I

In the formula (I)

n is 1 or 2,

R is in the meta or para position and is C ₃ -C ₆ alkyl or benzyloxy wherein the phenyl radical of the benzyloxy group is optionally substituted by fluoro or chloro,

R < ¹ > is hydrogen, methyl, chloro or fluoro,

R ² is hydrogen or C ₁ -C ₃ alkyl,

R ³ is hydrogen or C ₁ -C ₄ alkyl optionally substituted with hydroxy or methoxy,

R ⁴ and R ⁵ are independently hydrogen or C ₁ -C ₄ alkyl.

It is therefore an object of the present invention to provide a method of treating schizophrenia or anxiety as a psychiatric disorder that is present alone in a patient, as well as the treatment of schizophrenia and anxiety (i.e., accompanied by anxiety together with schizophrenia) Treatment.

According to the present specification and claims, an alkyl group may be a branched or linear chain group.

Pharmaceutically acceptable salts of the compounds of the present invention include, for example, inorganic acids such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, malonic acid, , Acid addition salts with organic acids such as citric acid, succinic acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Some of the compounds of formula I may have asymmetric carbon atoms and thus may exist as individual optically active isomers (enantiomers or diastereomers) or as mixtures thereof, including racemic mixtures. Accordingly, the present application and claims embrace all possible optically active isomers, and mixtures thereof, including racemic mixtures, within their scope.

It is a further object of the present invention to provide a method for treating schizophrenia and / or anxiety disorder, comprising administering to a patient in need thereof a therapeutic dose of an alpha -aminoamide of formula I as defined above, And / or anxiety, wherein the schizophrenia includes schizophrenia related disorders such as short-term psychotic disorders, delusional disorders, schizoaffective disorders and schizophreniform disorders, anxiety disorders include panic disorder , Obsessive compulsive disorder, post-traumatic stress disorder, social phobia or social anxiety disorder, specific phobias and generalized anxiety disorder.

Preferred compounds of formula (I)

n is 1 or 2,

R is in the meta or para position and is C ₃ -C ₆ alkyl or benzyloxy wherein the phenyl radical of the benzyloxy group is optionally substituted by fluoro or chloro,

R <^1> is hydrogen, methyl, chloro or fluoro,

R &lt; ² &gt; is hydrogen or methyl,

R ³ is hydrogen, methyl, ethyl, i-propyl, i-butyl, hydroxymethyl, methoxymethyl, 1 -hydroxyethyl or 2-hydroxyethyl, 1-methoxyethyl or 2-

R ⁴ and R ⁵ are independently hydrogen or C ₁ -C ₃ alkyl, optionally a single optically active isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

Examples of preferred compounds of formula (I) which may be used in effective amounts for the treatment of mental disorders which are schizophrenia and / or anxiety include,

2- [3- (2-fluorobenzyloxy) benzylamino] acetamide,

2- [4- (2-fluorobenzyloxy) benzylamino] acetamide,

2- [3- (3-fluorobenzyloxy) benzylamino] acetamide,

2- [4- (3-fluorobenzyloxy) benzylamino] acetamide,

2- [3- (2-chlorobenzyloxy) benzylamino] acetamide,

2- [4- (2-chlorobenzyloxy) benzylamino] acetamide,

2- [3- (3-chlorobenzyloxy) benzylamino] acetamide,

2- [4- (3-chlorobenzyloxy) benzylamino] acetamide,

2- [3- (2-fluorobenzyloxy) benzylamino] propanamide,

2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

2- [3- (2-chlorobenzyloxy) benzylamino] propanamide,

2- [4- (2-chlorobenzyloxy) benzylamino] propanamide,

2- [3- (3-fluorobenzyloxy) benzylamino] propanamide,

2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,

2- [3- (3-chlorobenzyloxy) benzylamino] propanamide,

2- [4- (3-chlorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [3- (2-fluorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [3- (2-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [3- (3-fluorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [3- (3-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,

2- [3- (2-fluorobenzyloxy) -4-fluoro-benzylamino] propanamide,

2- [4- (2-fluorobenzyloxy) -3-fluoro-benzylamino] propanamide,

2- [3- (2-fluorobenzyloxy) -4-methyl-benzylamino] propanamide,

2- [4- (2-fluorobenzyloxy) -3-methyl-benzylamino] propanamide,

2- [3- (3-fluorobenzyloxy) -4-fluoro-benzylamino] propanamide,

2- [4- (3-fluorobenzyloxy) -3-fluoro-benzylamino] propanamide,

2- [3- (3-fluorobenzyloxy) -4-methyl-benzylamino] propanamide,

2- [4- (3-fluorobenzyloxy) -3-methyl-benzylamino] propanamide,

2- [3- (2-fluorobenzyloxy) benzylamino] -N, N-dimethylpropanamide,

2- [4- (2-fluorobenzyloxy) benzylamino] -N, N-dimethylpropanamide,

2- [3- (3-fluorobenzyloxy) benzylamino] -N, N-dimethylpropanamide,

2- [4- (3-fluorobenzyloxy) benzylamino] -N, N-dimethylpropanamide,

2 - [[3- (2-fluorobenzyloxy) benzylamino] methylamino] propanamide,

2 - [[4- (2-fluorobenzyloxy) benzylamino] methylamino] propanamide,

2 - [[3- (3-fluorobenzyloxy) benzylamino] methylamino] propanamide,

2 - [[4- (3-fluorobenzyloxy) benzylamino] methylamino] propanamide,

2- [3- (2-fluorobenzyloxy) benzylamino] isovaleramide,

2- [4- (2-fluorobenzyloxy) benzylamino] isovaleramide,

2- [3- (3-fluorobenzyloxy) benzylamino] isovaleramide,

2- [4- (3-fluorobenzyloxy) benzylamino] isovaleramide,

2- [3- (2-fluorobenzyloxy) benzylamino] -3-hydroxy-propanamide,

2- [4- (2-fluorobenzyloxy) benzylamino] -3-hydroxy-propanamide,

2- [3- (3-fluorobenzyloxy) benzylamino] -3-hydroxy-propanamide,

2- [4- (3-fluorobenzyloxy) benzylamino] -3-hydroxy-propanamide,

2- [3- (2-fluorobenzyloxy) benzylamino] -3-hydroxy-butanamide,

2- [4- (2-fluorobenzyloxy) benzylamino] -3-hydroxy-butanamide,

2- [3- (3-fluorobenzyloxy) benzylamino] -3-hydroxy-butanamide,

2- [4- (3-fluorobenzyloxy) benzylamino] -3-hydroxy-butanamide,

2- [2- (4-pentylphenyl) ethylamino] propanamide,

2- [2- [3- (2-fluorobenzyloxy) phenyl] ethylamino] acetamide,

2- [2- [4- (2-fluorobenzyloxy) phenyl] ethylamino] acetamide,

2- [2- [3- (3-fluorobenzyloxy) phenyl] ethylamino] acetamide,

2- [2- [4- (3-fluorobenzyloxy) phenyl] ethylamino] acetamide,

2- [2- [3- (2-fluorobenzyloxy) phenyl] ethylamino] propanamide,

2- [2- [4- (2-fluorobenzyloxy) phenyl] ethylamino] propanamide,

2- [2- [3- (3-fluorobenzyloxy) phenyl] ethylamino] propanamide,

The present invention relates to a method for the preparation of the optically active isomer of 2- [2- [4- (3-fluorobenzyloxy) phenyl] ethylamino] propanamide, optionally with a single optically active isomer thereof or a mixture thereof or a pharmaceutically acceptable salt thereof .

More preferred compounds of formula (I)

n is 1,

R is in the meta or para position and is C ₃ -C ₆ alkyl or benzyloxy wherein the phenyl radical of the benzyloxy group is optionally substituted by fluoro,

R &lt; ¹ &gt; is hydrogen or methyl,

R &lt; ² &gt; is hydrogen,

R &lt; ³ &gt; is hydrogen, methyl, i-butyl or hydroxymethyl,

R &lt; ⁴ &gt; and R &lt; ⁵ &gt; are independently hydrogen or methyl, optionally a single optically active isomer thereof or a mixture thereof or a pharmaceutically acceptable salt thereof.

Examples of more preferred compounds of formula (I)

2- [3- (2-fluorobenzyloxy) benzylamino] acetamide,

2- [4- (2-fluorobenzyloxy) benzylamino] acetamide,

2- [3- (3-fluorobenzyloxy) benzylamino] acetamide,

2- [4- (3-fluorobenzyloxy) benzylamino] acetamide,

2- [3- (2-fluorobenzyloxy) benzylamino] propanamide,

2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

2- [3- (3-fluorobenzyloxy) benzylamino] propanamide,

2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [3- (2-fluorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [3- (2-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [3- (3-fluorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [3- (3-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,

2- [3- (2-fluorobenzyloxy) -4-methyl-benzylamino] propanamide,

2- [4- (2-fluorobenzyloxy) -3-methyl-benzylamino] propanamide,

2- [3- (3-fluorobenzyloxy) -4-methyl-benzylamino] propanamide,

2- [4- (3-fluorobenzyloxy) -3-methyl-benzylamino] propanamide,

2- [3- (2-fluorobenzyloxy) benzylamino] -N, N-dimethylpropanamide,

2- [4- (2-fluorobenzyloxy) benzylamino] -N, N-dimethylpropanamide,

2- [3- (3-fluorobenzyloxy) benzylamino] -N, N-dimethylpropanamide,

2- [4- (3-fluorobenzyloxy) benzylamino] -N, N-dimethylpropanamide,

2- [3- (2-fluorobenzyloxy) benzylamino] isovaleramide,

2- [4- (2-fluorobenzyloxy) benzylamino] isovaleramide,

2- [3- (3-fluorobenzyloxy) benzylamino] isovaleramide,

2- [4- (3-fluorobenzyloxy) benzylamino] isovaleramide,

2- [3- (2-fluorobenzyloxy) benzylamino] -3-hydroxy-propanamide,

2- [4- (2-fluorobenzyloxy) benzylamino] -3-hydroxy-propanamide,

2- [3- (3-fluorobenzyloxy) benzylamino] -3-hydroxy-propanamide,

2- [4- (3-fluorobenzyloxy) benzylamino] -3-hydroxy-propanamide,

2- [2- (4-pentylphenyl) ethylamino] propanamide,

2- [2- [3- (2-fluorobenzyloxy) phenyl] ethylamino] acetamide,

2- [2- [4- (2-fluorobenzyloxy) phenyl] ethylamino] acetamide,

2- [2- [3- (3-fluorobenzyloxy) phenyl] ethylamino] acetamide,

The present invention relates to a method for the preparation of 2- [2- [4- (3-fluorobenzyloxy) phenyl] ethylamino] acetamide, optionally with a single optically active isomer thereof or a mixture thereof or a pharmaceutically acceptable salt thereof, .

The most preferred compounds of formula (I)

n is 1,

R is in the meta or para position and is C ₃ -C ₆ alkyl or benzyloxy wherein the phenyl radical of the benzyloxy group is optionally substituted by fluoro,

R ¹ and R ² are hydrogen,

R &lt; ³ &gt; is hydrogen or methyl,

R &lt; ⁴ &gt; and R &lt; ⁵ &gt; are independently hydrogen or methyl, optionally a single optically active isomer thereof or a mixture thereof or a pharmaceutically acceptable salt thereof.

Examples of the most preferred compounds of formula (I)

2- [4- (2-fluorobenzyloxy) benzylamino] acetamide,

2- [4- (3-fluorobenzyloxy) benzylamino] acetamide,

2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,

2- [4- (2-fluorobenzyloxy) -3-methyl-benzylamino] propanamide,

2- [4- (3-fluorobenzyloxy) -3-methyl-benzylamino] propanamide,

2- [4- (2-fluorobenzyloxy) benzylamino] -N, N-dimethylpropanamide,

2- [4- (3-fluorobenzyloxy) benzylamino] -N, N-dimethylpropanamide,

2- [2- (4-pentylphenyl) ethylamino] propanamide, optionally a single optically active isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

Certain compounds of formula I that are particularly effective for use in the treatment of psychotic disorders that are schizophrenia and /

(S) - (+) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

(S) - (+) - 2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,

(R) - (-) - 2- [4- (3-fluorobenzyloxy) benzylamino] propanamide, and a pharmaceutically acceptable salt thereof, preferably methanesulfonic acid.

Biological activity

The compounds of the present invention have a number of mechanisms including NMDA antagonism, MAO-B inhibition, glutamate release inhibition, DA reuptake inhibition and sodium and / or calcium channel blockade.

Representative compounds of the present invention are "Ralphinamide", ie, (S) - (+) - 2- [4- (2- fluorobenzyloxy) benzylamino] propanamide, 4 and 5) and anxiety (Examples 6 and 7) animal models. This effect is surprising considering the lack of antagonistic effects on dopamine receptors (Example 1) and its significant inhibitory activity against MAO-B, an enzyme that regulates dopamine metabolism (Example 2). Inhibition of these enzymes increases dopamine levels in the brain. Indeed, selective MAO-B inhibitors are known to be used in Parkinson's disease because they can increase dopamine concentrations.

Ralphinamide is a potent MAO-B inhibitor with high brain permeability and can be expected to have a deleterious effect on schizophrenia.

Furthermore, it has been shown that Ralphinamide is an NMDA antagonist (Example 3), which would be another negative feature for schizophrenia treatment given the hypothesis of glutamate dysfunction in schizophrenia as described above. For all these reasons, the efficacy of ralphinamide in the schizophrenia model is an unexpected discovery.

The binding of the Ralphine amide dopamine receptor (D1, D2L, D2S, D3, D4.2, D4.4, D4.7 and D5) is determined by radioligand analysis (Example 1).

The MAO-B activity of the ralphinamide is determined using a radioactive enzyme assay in the rat brain mitochondria (Example 2).

Ralphinamide inhibition of the NMDA receptor complex is measured as described in Example 3. [

Anti-schizophrenic activity is assessed using the model "Pre-pulse suppression of surprise in mice (PPI)" (Example 4) and the "MK-801 induced motility in mice" (Example 5) model.

Anti-anxiety activity is measured using the "Anxiety Open-Field Test" (Example 6) and "Bead Screening Test" (Example 7) in rats.

The compounds of the present invention are active in vivo when administered in the range of 0.1-200 mg / kg orally, intraperitoneally or intravenously in various animal models described below.

The compounds of the present invention may advantageously be used in combination with one or more other therapeutic agents effective in the treatment of schizophrenia and / or anxiety. Examples of therapeutic agents suitable for adjunct therapy include serotonin receptor modulators; AMPA modulators; Nicotinic receptor agonists; Tricyclic antidepressants (e.g., amitriptyline); Monoaminergic absorption inhibitors (such as venlafaxine); Cholinesterase inhibitors; Antipsychotic drugs including orthopedic and atypical antipsychotic drugs (eg haloperidol, risperidone, clozapine); Selective serotonin reuptake inhibitors, antidepressants such as serotonin and noradrenaline reuptake inhibitors; Tricyclic antidepressant drugs; Mood stabilizers (such as lithium, lamotriene, valproate); Anxiolytic agents such as benzodiazepines, buspirone, beta-adrenergic receptor antagonists; Other calcium or sodium channel blockers are included.

The compounds of the invention are useful in human and veterinary medicine. The term "treatment ", as used herein, unless otherwise specifically defined, includes the prevention, alleviation and treatment of pathological diseases, particularly those which involve both established and prophylactic treatment of established symptoms. The compounds of the invention for use in the treatment or prophylaxis in the above-mentioned pathology will preferably be used as active ingredients in pharmaceutical compositions.

It is therefore a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a salt thereof together with a pharmaceutically acceptable carrier.

Thus, the term "therapeutic dose" used when referring to a "quantity", "dose" or "dose" of a compound of the invention refers to both the therapeutic and prophylactic treatment of established symptoms of the pathological disorder Quot ;, "dose" or "dose"

The pharmaceutical compositions of the present invention may be administered in a variety of immediate and modified release formulations, such as tablets, troches, capsules, dragees or film-coated tablets, liquid solutions, oral formulations in the form of emulsions or suspensions, rectal formulations in the form of suppositories, And / or topical and transdermal formulations in the form of parenteral, intravenous, or infusion formulations, intranasal formulations, patches, gels, and creams in the form of depot compositions.

Suitable pharmaceutically acceptable therapeutically inert organic and / or inorganic carrier materials useful in the manufacture of such compositions include, for example, water, gelatin, gum arabic, lactose, starch, cellulose, magnesium stearate, talc, vegetable oil, cyclodextrin , Polyalkylene glycols and the like.

Aminoamide derivatives of formula (I) as defined above may be sterilized and may be sterilized and mixed with a preservative, stabilizer, wetting or emulsifying agent such as paraffin oil, mannitol monooleate, salts for adjusting osmotic pressure, May contain additional well known components such as &lt; RTI ID = 0.0 &gt;

For example, solid oral formulations may contain, together with the active ingredient, a diluent such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; Lubricants such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycol; Binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; Disintegrants such as starch, alginic acid, alginate or sodium starch glycolate; Effervescent mixture; dyes; Sweetener; Wetting agents such as lecithin, polysorbate, lauryl sulfate; And non-toxic pharmacologically inert materials commonly used in pharmaceutical formulations. Such pharmaceutical preparations can be prepared by known methods such as mixing, granulating, tabletting, sugar-coating or film-coating processes.

The preparation of the pharmaceutical composition of the present invention can be carried out according to conventional techniques.

Oral formulations include, for example, sustained release formulations that can be prepared in conventional manner by applying enteric coatings to tablets and granules.

Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions. Syrups may contain, for example, saccharose as a carrier, or saccharose with glycerin and / or mannitol and / or sorbitol.

Suspensions and emulsions may contain as carrier, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The intramuscular injection suspension or solution may contain a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, a glycol (e.g., propylene glycol), and, if desired, an appropriate amount of lidocaine hydrochloride can do. The solution for intravenous injection or infusion may contain, for example, aseptic water as a carrier or preferably in the form of a sterile aqueous isotonic saline solution.

The suppository may contain a pharmaceutically acceptable carrier together with the active ingredient, for example, cocoa butter, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

A pharmaceutical composition comprising an alpha -aminoamide derivative of formula (I) as defined above is prepared by dissolving one or more active ingredient (s) in a unit dose of from about 0.1 to about 100 mg, based on the unit dose of, for example, capsules, tablets, teaspoonfuls, About 500 mg, and most preferably 1 to 10 mg.

The optimal therapeutically effective dose will be readily determinable by one of ordinary skill in the art and will basically depend upon the strength of the formulation, the mode of administration, and the condition or disorder being treated. It is also necessary to adjust the dose to an appropriate therapeutically effective level depending on factors associated with the particular patient being treated, such as the age, weight, diet, and time of administration of the patient.

While the invention has been described in conjunction with the preferred embodiments thereof, those skilled in the art will appreciate that other aspects may be practiced without departing from the spirit of the invention.

Example 1

Dopamine receptor binding assay

- Radioactive ligand binding assay

The assay is performed under standard conditions as described in the following references (see Dearry A et al., Nature; 1990; 347: 72-76; Bunzow JR et al., Nature; 1988; 336: 783-787 Nature, 1992; 358: &lt; RTI ID = 0.0 &gt; 149- &lt; / RTI &gt;152; Sibley DR et al., Trend Pharmacol. Sci .; 1992; 13: 61-69).

Biochemical analysis results are expressed as percent inhibition of specific binding at single compound concentration. The reaction is considered to be significant for binding activity in excess of 50%.

Ralphine amide as the methanesulfonate salt does not show significant binding to dopamine receptors, as shown in Table 1.

Table 1

Example 2

In vitro activity of MAO-B enzyme

- Membrane preparation (crude mitochondrial fraction)

Male Whister rats (Harlan, Italy, weight 175-100 g) are sacrificed under mild anesthesia, brain is rapidly removed and homogenized in 8 volumes of ice-cold 0.32M sucrose buffer (pH 7.4) containing 0.1M EDTA. The coarse homogenate is centrifuged at +2 ° C for 10 minutes at +2 ° C and the supernatant is recovered. The pellet is homogenized and centrifuged again. The two supernatants are pooled and centrifuged at 9,250 rpm for 10 minutes. The pellet is resuspended in fresh buffer and centrifuged at + 4 ° C at 11,250 rpm for 10 minutes. Store the resulting pellet at -80 占 폚.

- Enzyme activity analysis in vitro

Enzyme activity is assessed by radioactive enzyme assay using substrate ¹⁴ C-phenylethylamine (PEA) for MAO-B.

The mitochondrial pellet (500 단백질 protein) is resuspended in 0.1 M phosphate buffer (pH 7.4). 500 μl of this suspension is added to 50 μl of test compound solution or buffer, and incubated at 37 ° C. for 30 minutes (preliminary incubation), followed by addition of substrate (50 μl). The cultivation is carried out at 37 ° C for 10 minutes ( ¹⁴ C-PEA, 0.5 μM).

The reaction is stopped by adding 37% HCl or 0.2 ml perchloric acid. After centrifugation, the desaminated metabolite is extracted with 3 ml of toluene (PEA) and the radioactive organic phase is measured by liquid scintillation spectrometry at 90% efficiency. By measuring the radioactivity of the eluate, the amount of neutral and / or acidic metabolite formed as a result of MAO activity is obtained.

The activity of MAO in the sample, corresponding to the percentage of radioactivity compared to the control activity in the absence of inhibitor, is expressed as converted substrate (nmole) / protein (mg) / min.

The drug inhibition curves are obtained twice each from at least 8 different concentration points (10 ^-10 to 10 ^-5 M). The IC ₅₀ value (drug concentration that inhibits enzyme activity by 50%) is calculated as the confidence interval measured using a nonlinear regression analysis (best-fit secondary computer program).

In an in vitro enzyme study using rat brain mitochondria, the ralphinamide methanesulfonate salt strongly inhibits MAO-B with an IC ₅₀ of 132 nM.

Example 3

Inhibition of the NMDA receptor complex

Materials and methods for patch clamp experiments on NMDA receptors

Cell production and culture

Processes involving animals and their management are covered by national (DL n.116, GU, suppl.40, Feb. 18, 1992) and international laws and policies (EEC Council directive 86/609, OJL358.1, Dec.12 1987; The National Institutes of Health, the National Institutes of Health, and the National Institutes of Health.

Cortical neurons are prepared from fetal Wistar rats (E17-E19). Female rats on days 17-19 of pregnancy are anesthetized and sacrificed. Fetuses (n = 4-5) were excised and incubated with ice-cold Hank's solution (Hank's solution (Life tech.14170-088) + glucose 30% + Pen-Strep 100x (Life Tech. 15140-122) Mu] g / ml and 5 [mu] M Hepes-NaOH.

The fetal brain is cut in half, each cortex is cut into smaller pieces with scissors, the pieces are transferred to a 15 ml centrifuge tube using a 5 ml pipette and washed twice with Hank's solution.

The solution is removed except 1 to 2 ml, the tissue is first separated with a 5 ml pipette and then separated into two flame-polished Pasteur pipettes (middle and small holes, respectively).

After mechanical separation, 5 ml of Dulbecco's modified Eagle medium (Gibco 41966-029) + FBS (Hyclone) 10% + Glutamine (Life Tech. 25030-024) 2 mM + Pen-Strept 100 U- And the cell suspension is centrifuged at 1,000 rpm for 5 minutes. The supernatant is removed and 5 ml of complete NB medium is added [NB medium (Life tech.21103-049) + B27 (Life tech.17504-044) 2% + glutamine 2mM + pen-strip 100U-100 Mu] g / ml).

Cells are counted and diluted in NB medium at a concentration of 400,000 cells per petri dish treated with 5 [mu] g / ml poly-D-lysine.

Cortical neurons are used in patch clamp experiments from day 6 to day 11 after plate culture.

Whole cell patch clamp record

Experiments on cortical neurons are performed using a standard whole cell patch clamp method (Hamill et al., 1981. Pfugers Arch., European Journal of Physiology 391 (2): 85-100). The membrane current is recorded and filtered at 5 kHz with an Axon Axopatch 200B amplifier and the data is digitized with Axon Digidata 1322 A (Axon Instruments, CA, USA). Protocol execution and data acquisition are controlled online with the Axon pClamp8 software. The measurement and reference electrode is an AgCl-Ag electrode. Sutter Instrument P-87 Puller (CA, USA) is used to pull a patch clamp pipette with a resistance of 2-3 MΩ from a Harward borosilicate glass tube. The cells are subsequently thawed with the extracellular solution using the solution changer Biologic RSC-200.

Solutions and medicines

The external control solution (without MgCl ₂ ) consists of NaCl 155, KCl 2, CaCl ₂ 0.5, HEPES 10, and glucose 10 (mM). MgCl ₂ is excluded to avoid its voltage dependent blocking.

To stimulate the NMDA current, NMDA and glycine are used as agonists and co-activators, respectively, in an external bath solution (N-methyl-d-aspartic acid Sigma M-3262; glycine Bio Rad 161-07118). Various concentrations are used according to the experimental protocol as described in the RESULTS chapter. TTX 1 [mu] M (TTX Sigma T-8024) and Stricinin 5 [mu] M (Strychnine Sigma S-8753) also exist to block Na channel and glycine receptor activity, respectively.

The internal solution contains CsCl 65, CsF 65, NaCl 10, CaCl ₂ 1.3, MgCl ₂ 2, HEPES 10, EGTA 10, MgATP 1 (mM).

A stock solution (10 mM) of ralphinamide methanesulfonate is prepared in Milli-Q H ₂ O and diluted to the final concentration in an external solution.

Data analysis

Data are analyzed using Clampfit 9 (Axon Instruments, CA) and Origin 7.5 (Microcal Inc., Northampton, MA, USA) software. Data points and results are expressed as arithmetic mean ± SE.

In all experiments, -70 mV is used as the holding potential. Unless otherwise specified, the control NMDA current is activated by NMDA 100 [mu] M + 10 [mu] M glycine. Ralphine amide blockade yields the NMDA current after 1 minute-preliminary incubation of the compound as a decrease relative to the NMDA currents obtained simultaneously in the drug-free control condition. The fractionation block is plotted against the drug concentration to obtain a drug concentration-inhibition curve. Dose-response curve is then fit using the following logistic equation: y = A2 + (A1 - A2) / [1 + (x / IC 50) p]. Is a fixed value of 0 and 1 A1 and A2 corresponding to the 0 and 100% current inhibition, x is the drug concentration, IC ₅₀ is the drug concentration which produces 50% inhibition current, p is the corresponding slope factor that.

Ralphinamide methanesulfonate salts inhibit NMDA-induced currents in the primary cortical neurons of rats with an IC ₅₀ of 7.3 μM.

Example 4

Pre-pulse inhibition of surprise in mice with destruction by NMDA receptor antagonism

Pre-pulse inhibition (PPI) is a phenomenon that transcends species (that is, a phenomenon that exists in mammals ranging from mice to humans), but is relatively lacking in schizophrenia patients. PPI procedures are used to assess patients' ability to "block" or filter out environmental information. In the hearing (surprise model) of sensory gating, weak auditory stimuli (full pulses) reduce the reflex jerking response (surprise) caused by the second stronger stimuli (pulses). Drugs such as dinofil- lin (MK-801) or amphetamine disrupt PPI and represent an animal model of schizophrenia. Antipsychotic drugs can prevent PPI deficiency. This test is very useful for screening potential antipsychotic drugs.

Method: Male Whister rats weighing 200-300 g are used. Apparatus: All surprises and PPI tests are carried out in four surprise chambers. Each chamber contains a transparent, unrestricted Plexiglas cylinder that is ventilated, illuminated, soundproofed, and placed on a platform. The high-frequency loudspeaker inside the chamber generates 70dB of continuous background noise and various auditory stimuli. The vibration of the plexiglass cylinder caused by the animal's surprise reaction is converted to an analog signal by a piezoelectric device attached to the platform. These signals are then digitized and stored in a computer. Starting at the onset of stimulation, 65 recordings are performed at 1 ms intervals and the auditory surprise response is measured using the average amplitude. The sound level is given in dB.

Pre-pulse suppression session: Two types of auditory stimulation are used after five minutes of adaptation (background white noise, 70 dB): auditory stimulation alone (120 dB, 40 ms) , 82dB, 40ms). During each experimental session, 20 trials of each type are performed with inter-stimulus intervals of 20 seconds. For each individual animal, the amplitudes for two types of trials (stimuli driven by either single stimuli or previous pulses) are separately averaged. The degree of total pulse suppression is obtained by dividing the difference between the size of the pulse alone (P) and the size of the previous pulse plus the pulse duration (PP + P) by the size of the pulse alone and multiplying by 100, P] × 100)) (PPI (%))). A high value of the calculated PPI (%) indicates that the former pulse inhibited the response to the pulse stimulation, while a lower value indicates that the inhibition by the previous pulse is weaker. Materials and Treatment: 0.2 mg / kg of MK-801 is dissolved in saline and administered intraperitoneally. In each experiment, mice are dosed for administration of a compound of the present invention or an excipient and tested using an inter-individual experimental design in a PPI session. The order of drug treatment for the first experiment is the test compound followed by MK-801. In the second experiment, the test compound and then amphetamine are administered to the rats.

Statistical Analysis: Dunnett post-test is performed after multiple ANOVA.

As shown in Table 2, orally administered ralpinamide methanesulfonate salt in this experimental model was found to have an activity of reversing the destructive effect of MK-801 on PPI at a dose of 90 mg / kg.

Table 2

Effect of ralphinamide methanesulfonate on MK-801-induced PPI breakdown

모든 데이타는 산술 평균±SEM로 표시한다.

All data are expressed as mean ± SEM.

# Indicates a statistically significant difference in percent inhibition between excipient and vehicle-treated animals and animals injected with MK-801.

* Represents a statistically significant difference between the excipient + MK-801 treated animal and the ralphinamide amethanesulfonate treated animal. Variance analysis follows the Dunnett test.

Example 5

MK-801 induced hyperactivity in mice

Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) or MK-801 cause behavioral disorders such as schizophrenia-like symptoms in humans and hyperactivity in animals. Atypical antipsychotic drugs reduce hyperactivity caused by MK-801 or PCP in mice, which represents an animal model commonly used to predict the inhibitory effect of schizophrenia symptoms. The excipient or compound is injected 30 to 35 minutes before placing the animal in the activity chamber. Administration of MK-801 (0.3 mg / kg) 15 minutes before placing the animal in the activity chamber (i.e., 20 to 45 minutes after the injection of the vehicle or compound) caused hyperactivity in the mouse, Measure the moving distance (cm). The active compound attenuates the increase in total travel distance induced by MK-801.

Example 6

Anxiety open-field test

The open field test is commonly used to evaluate exercise, inquiry, and anxiety-like behavior in rats and mice. This test is particularly useful for assessing anxiety relief and the effects of anxiety-inducing drugs, exercise responses to drugs, and behavioral responses to the new.

The open field challenge approaches the conflict between the inherent horror of the rat in the central area of the open or lighted open field and the aspirations of those who wish to explore the new environment. The inherent tendency to see rodents when they are anxious is to stay close to the walls (contact nature). At this point, anxiety-related behaviors are measured to the extent that the rat deviates from the center of the open field test.

The open stage consists of an empty bright square stage surrounded by a wall to prevent the animal from escaping. The stage (90 cm × 90 cm × 40 cm height) is divided into a 6 × 6 grid of the same size using a black tape.

Define the sum of all the squares adjacent to the wall (ie, 16 rectangles, excluding four corners of the 36 squares) as the outer area of the box. The central area of the box (16 squares) is divided into a large center (LC) and a small center (SC) consisting of 12 and 4 squares, respectively.

The rat is placed in the center of the stage and his behavior is recorded and scored videotaped over a selected period (5-15 minutes).

Record the time spent within each square category. In addition, the 15 minute open field test is divided into three blocks of 5 minutes, and the total motor activity is scored as the number of squares entering each 5 minute block. In addition, record the frequency of the following behaviors: a stretching posture (stretching the front leg to stretch forward, often flexing the back to maintain a low posture), lifting the front leg (standing on the side of the stage, (Use your feet or tongue to clean or scrape your body) and cornering (ie, standing or sitting facing the corner of the box). Finally, the latency period for locating either the center or the four corners is manually scored.

Compared to control rats trying to stay on the wall, the rats that received the anti-anxiety compound explored the center of the open field.

Example 7

Beading test

Consider a bead screening test as an animal model of anxiety / obsessive compulsive disorder (OCD). Mice, each of which is contained in several glass beads, tend to unconsciously hide glass beads.

Some compounds that alleviate anxiety, depression, mental illness, or obsessive-compulsive disorders affect this behavior and reduce the number of hidden beads. Thus, the test has predictive validity for anti-anxiety and anti-OCD latent compounds.

CD1 mice are injected with 10, 30, 60 and 80 mg / kg doses (po) of rosin amide, 10 mg / kg dose (sc) of fluoxetine (FLX), or saline and returned to us. After 30 minutes (ralphinamide) or 60 minutes (fluoxetine), place each mouse separately in a new glass of 12 glass beads evenly spaced. After 30 minutes, we take out the mouse and count the number of glass beads hidden in the sawdust over 2/3. Figure 1 shows the effect and statistical evaluation of the ralphinamide in the bead screening test measured under the following conditions.

Bonferroni multiple comparison test after member ANOVA; N = 6 to 8 mice per group, ^* p < 0.05 for control group; p ^*** < 0.001

CTR: Control

FLX: Fluoxetine treated group (10 mg / kg, sc.)

Figure 1 demonstrates that ralphinamide significantly decreases the number of beads hidden at a dose (po) of 80 mg / kg.

Claims (30)

(S) - (+) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide,
(S) - (+) - 2- [4- (3-fluorobenzyloxy) benzylamino] propanamide,
(R) - (-) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide and
An anxiety disorder or schizophrenia, comprising a compound selected from (R) - (-) - 2- [4- (3- fluorobenzyloxy) benzylamino] propanamide or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for the treatment of psychotic disorders accompanied by anxiety,
Wherein said schizophrenia comprises schizophrenia-related disorders such as short-term psychotic disorders, delusional disorders, schizoaffective disorders and schizophreniform disorders,
Wherein the anxiety disorder comprises panic disorder, obsessive compulsive disorder, post-traumatic stress disorder, social phobia or social anxiety disorder, specific phobia and generalized anxiety disorder. The pharmaceutical composition according to claim 1, comprising a compound (S) - (+) - 2- [4- (2-fluorobenzyloxy) benzylamino] propanamide or methanesulfonate thereof. 3. A pharmaceutical composition according to claim 1 or 2, for use in the treatment of psychotic disorders which are schizophrenia. 3. The pharmaceutical composition according to claim 1 or 2 for use in the treatment of anxiety disorder. 3. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of psychotic disorders accompanied by anxiety with schizophrenia. 3. The pharmaceutical composition according to claim 1 or 2, which is administered together with one or more other therapeutic agents effective for the treatment of schizophrenia or anxiety. 3. A pharmaceutical composition according to claim 1 or 2, which is administered with one or more other therapeutic agents selected from orthostatic and atypical antipsychotic drugs, mood stabilizers, serotonin receptor modulators, nicotinic receptor agonists and cholinesterase inhibitors, Or for the treatment of anxiety accompanying schizophrenia. 3. A pharmaceutical composition according to claim 1 or 2, for use in the treatment of anxiety, or anxiety accompanying schizophrenia, administered together with one or more other therapeutic agents selected from an anxiolytic agent. The pharmaceutical composition according to claim 7 for use in the treatment of anxiety accompanying schizophrenia or schizophrenia, wherein said another therapeutic agent selected from orthostatic and atypical antipsychotic drugs is haloperidol or risperidone. 10. A pharmaceutical composition according to claim 9 for use in the treatment of anxiety accompanying schizophrenia or schizophrenia, wherein said another therapeutic agent is haloperidol. 8. A pharmaceutical composition according to claim 7 for use in the treatment of schizophrenia or anxiety accompanying schizophrenia, wherein said another therapeutic agent is a mood stabilizer selected from lithium, lamotrigine and valproate. 9. The pharmaceutical composition according to claim 8, wherein said another therapeutic agent is an anxiolytic selected from benzodiazepines, buspirone and beta-adrenergic receptor antagonists, anxiety disorders, or schizophrenia associated anxiety disorders. 3. The pharmaceutical composition according to claim 1 or 2, comprising 0.1 to 500 mg of active ingredient per unit dose. 14. A pharmaceutical composition according to claim 13 comprising from 1 to 10 mg of active ingredient per dose unit. 3. The pharmaceutical composition according to claim 2, which is administered together with one or more other therapeutic agents effective for the treatment of schizophrenia, anxiety, or anxiety accompanying schizophrenia. 16. The use according to claim 15 for the treatment of schizophrenia or anxiety accompanying schizophrenia, which is administered with one or more other therapeutic agents selected from orthostatic and atypical antipsychotic drugs, mood stabilizers, serotonin receptor modulators and cholinesterase inhibitors A pharmaceutical composition for use. 16. A pharmaceutical composition according to claim 15, for use in the treatment of anxiety, or anxiety accompanying schizophrenia, which is administered with one or more other therapeutic agents selected from anxiolytics. 17. The pharmaceutical composition according to claim 16 for use in the treatment of anxiety accompanying schizophrenia or schizophrenia, wherein said another therapeutic agent selected from orthostatic and atypical antipsychotic drugs is haloperidol or risperidone. 19. The pharmaceutical composition according to claim 18 for use in the treatment of anxiety accompanying schizophrenia or schizophrenia, wherein said another therapeutic agent is haloperidol. 17. The pharmaceutical composition according to claim 16, wherein the other therapeutic agent is a mood stabilizer selected from lithium, lamotrigine and valproate, for use in the treatment of schizophrenia, or anxiety accompanying schizophrenia. 18. The pharmaceutical composition according to claim 17, wherein said another therapeutic agent is an anxiolytic selected from benzodiazepines, buspirone and beta-adrenergic receptor antagonists, anxiety disorders, or anxiety accompanying schizophrenia. 3. The pharmaceutical composition according to claim 2, comprising from 0.1 to 500 mg of active ingredient per unit dose. 3. The pharmaceutical composition of claim 2 comprising from 1 to 10 mg of active ingredient per dose unit. delete delete delete delete delete delete delete

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